Alkyl isoquinolinium phenates



United Stat 3,285,923 ALKYL ISOQUINOLINIUM PHENATES Reginald L. Wakeman, Philadelphia, Pa., and Joseph F.

Coates, Washington, D.C., assignors, by mesne assignments, to Millrnaster Onyx Corporation, New York,

N .Y., a corporation of New York No Drawing. Filed July 3, 1963, Ser. No. 292,764 29 Claims. (Cl. 260-286) The object of the present invention is the preparation of compounds by reaction of N-alkyl isoquinolinium quaternary ammonium hydroxides or their salts of inorganic acids, in which the alkyl radical has from 8 to 18 carbon atoms, with phenols or substituted phenols or with water-soluble salts of such phenolic compounds. It is a further object of this invention to prepare microbiologically active compounds.

It has generally been thought that quarfernary ammonium compounds which are microbiologically active are incompatible, that is to say, lose their microbiological activity in the presence of anionic materials.

We have discovered, however, contrary to general belief, that the reaction of micro biologically active Watersoluble quaternary ammonium compounds of the alkyl isoquinolinium type with phenols, substituted phenols or their Water-soluble salts and with thiophenols and their salts yields products which, in many cases, are equally as active, microbiologically, as the parent quaternary ammonium compounds from which they are derived. In some cases they are more active. As suitable phenols we may employ any monohydric or polyhydric phenol which is free from carboxyl groups or sulfonic acid groups. The phenol may have one or more benzene rings or it may have condensed ring systems. Examples of such phenols are phenol itself; the isomeric cresols; xylenols; catechols; catechol ethcrs; resorcinols and alkylated resorcinols, such as hexyl resorcinol and phloroglucinol; isopropyl phenols; t-butyl phenols: 4- methyl-6-t-butyl phenol; di-t-butyl-p-cresol; higher alkyl phenols such, for example, as octyl phenol and nonyl phenol, o-phenyl phenol, p-phenyl phenol, 2,2'-methylene bis 4-ethyl-6-t-butyl phenol; derivatives of the foregoing compounds free from carboxyl and sulfonic acid groups; the various halo phenols; hal-o cresols; halo xylenols; halo catechols; and their analogs and homologs; methoxy phenols and higher alkoxy phenols together with corresponding alkylated homologs; amino phenols; bromo phenols and their corresponding methyl, polymethyl and alkyl homologs; nitro phenols, nitro cresols, nitro xylenols, salicyalaldehyde; esters of phenolic acids, such as p-hydroxy methyl benzoate, p-hydroxy ethyl benzoate, p-hydroxy propyl benzoate, p-hydroxy butyl benzoate, p-hydroxy benzyl benzoate which may also be designated, respectively, as paracarbomethoxy phenol, para carboethoxy phenol, paracarbopropoxy, phenol, paracarbobutoxy phenol, paracarbobenzoxy phenol; naphthol and the chloro naphthols, alkyl naphthols, amino naphthols and the like; hydroxy diphenyl, hydroxy diphenyl ether, hydroxy diphenylene oxide, 2,2-dihydroxy-5,5'- dichloro diphenyl methane and the like. In general, any phenolic compound may be employed which is free from carboxylic and sulfonic acid groups.

The phenols are preferably reacted in the form of their Water-soluble salts such as their sodium, potassium or ammonium salts or in the form of the free phenols if solubility relationships permit.

Quaternary ammonium compounds useful in this in- 3,285,923 tov. 15, 1966 vention are higher alkyl isoquinolinium halides corresponding to the formula:

R N X wherein X is a halogen atom such as bromine or chlorine, or a hydroxyl group and R is an alkyl radical having from 8 to 18 carbon atoms, preferably having 12 to 16 carbon atoms. Typical examples are lauryl isoquin olinium chloride, bromide or hydroxide, the correspond ing myristyl and cetyl compounds, or mixtures thereof.

A further feature of our invention is to be found in the new physical properties, especially the low water solubility of our preferred compounds, generally not in excess of 3 parts by weight per parts of solution at room temperatures, so that they are especially useful in applications wherein the known water-soluble quaternary ammonium compounds are Washed away or are physically incompatible or unsatisfactory because of their high water solubility. It is, of course, possible to promote water solubility by the use of suitable solvents, coupling agents or dispersing agents. Furthermore, when an excess of either quaternary or phenolic compound is employed, the resultant compound may be soluble in aqueous solutions of the excess reactant.

The compounds may be prepared by mixing aqueous solutions of the quaternary ammonium salts with any of the aforementioned phenols, their analogs or homologs, or with a salt thereof. In the case of polyhydric phenols such, for example, as resorcinol, phloroglucinol or pyrogallol, they may be employed in the form of their completely neutralized salts or in any desired degree of neutralization, i.e., mono, di, trisodium salts or the like.

After thoroughly mixing, the organic product layer is separated from the aqueous layer (as with a separatory funnel) since two distinct phases are for-med. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or unreacted materials. The solvent, if any, may be evaporated and the product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in which the starting materials are soluble will be satisfactory. Non-aqueous solvents facilitate the separation of by-product inorganic salt and reduce the need for vacuum drying to get an anhydrous product. When a non-aqueous medium is employed, it is usually necessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrapped water is irrelevant to the microbiological activity of the compounds. In other applica tions, removal of water may be essential for reasons not related to biological activity.

An alternative method for the preparation of compounds especially applicable to the t reatmen t oflfabri 4:1:--- Mam...

pound .reacting with the anionic moiety, depositing the product in the most intimate way on the surface and in the interstices, convolutions and reticulations of the material.

The adjustments of solution concentration to achieve the required pickups are well known to those skilled in the art. The order of treatment may be reversed without affecting the biological activity or durability of the product on the material. They may be formulated as water dispersions by dissolving them in a water-miscible organic solvent such as acetone or methanol and diluting with water, or by dissolving them in emulsifiable oils such as, for example, sulfonated castor oil or pine oil and diluting with water. In preparing aqueous dispersions, emulsifying agents such, for example, as ethylene oxide condensates of alkyl phenols may be used with or without organic solvents.

It is surprising that the compounds of this invention exhibit high microbiocidal activity despite their relative insolubility in water. Because of their unusual combination of physical and microbiological properties, they can be used to impart laundry-resistant anti-microbial charac teristics to textiles. They can also be used as the active agent in anti-mildew finishes for textiles which are resistant to leaching with water.

Although the compounds have low Water solubility, they are compatible with various organic solvents, plasticizers and high molecular weight compounds. Consequently, they may be incorporated as anti-microbial agents in synthetic resins and plastics. The compounds are compatible with natural and synthetic rubber latices. Therefore, they may be used to prepare bacteriostatic films and molded objects deposited from such latices.

The compounds can be incorporated into cutting and grinding fluids without precipitation. Also, they blend well with non-ionic and anionic surface-active agents. In such compositions they retain their microbiological activity.

It will be understood that the properties of the products described herein will vary depending upon the nature of the alkyl isoquinolinium compound used in their preparation as well as the phenolic compound reacted therewith.

The chemical, physical and biological properties of the products of our invention make them especially appro priate for the following applications when suitably incorporated in active amounts in an appropriate vehicle, binders, medium or substrate:

(1) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails, tenting and other woven and non-woven reticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of microorganisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppressant for shoes and other leather products.

(6) Topical antiseptics.

(7) Antidandrutf agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement brick and other inorganic building materials, to retard growth of microorganisms, fungi, mold and algae.

(11) Wool preservative.

(12) Plant and tree spray to combat fungi.

(1,3) Antimycotic agents for soap wrappers.

(l4) Self-sanitizing brushes.

(15) Mildewproofing agent in and on plastic and film.

(l6) Mildewproofing of cellulosics, cardboard, fibreboard,

paper and cordage.

(17) Contact biostat for application to film, waxes and cloth to preserve cheese, meats, vegetables and other food products.

(l8) Algal inhibition, especially on surfaces and in solution'where low foaming is desirable.

(19) Paper pulp slime control.

(20) Egg preservation.

(21) Sanitizing agent for rug, carpet, curtains.

(22) Adhesive preservation.

(23) Preservation of latex paints.

The products of this invention are particularly useful in that they provide a single chemical compound which has a broad spectrum of microbiocidal activity, aflinity and substantivity for hair and scalp which can be used for treatment of dermatological disorders of the scalp such, for example, as dandruff. In vitro tests show them to be especially active with respect to Pityrosporum ovale.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard Tube Dilution Test, the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This test is used to determine the lowest concentration of microbiologically active compounds which will inhibit the growth of the organism in question. For wide range of applications, the inhibition of growth rather than outright kill is satisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the microbiologically active compound at an appropriate concen tration is added to the test tube which is then inoculated with 0.1 cc. of a twenty-four hour old culture of the organism under study. The test tube is then incubated at 37 C. for forty-eight hours and observed for bacterial growth.

The same procedure is followed for fungi. In such tests, however, the tubes are incubated for fourteen days at a temperature suitable for optimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the following examples:

Example I A stock solution containing 10 weight percent of sodium pentachlorophenol was prepared. An aliquot of the solution containing 0.030 equivalents of sodium pentachlorophenol was vigorously agitated while a chemically equivalent amount of a commercial grade of lauryl isoquinolinium bromide (Onyx Chemical Corporation; Isothan Q-) in the form of a 10 weight percent solution was slowly added. The mixture was then poured into a separatory funnel. The mixture separated into two phases. The organic product layer was removed and vacuum dried to yield a dark brown paste in 83% yield. The product was lauryl isoquinolinium pentachlorophenate.

Example 11 A solution was prepared containing 10 weight percent of the sodium salt of chloro o-phenyl phenol. To a vigorously agitated aliquot of this solution containing 0.044 equivalent Weights of the compound was added a chemically equivalent amount of a 10% solution of lauryl isoquinolinium bromide. The mixture was poured into a separatory funnel and shaken, after which it was allowed to stand until it separated into two phases. The organic product layer, a brown oil, was drawn OE and vacuum dried to yield a brown paste of lauryl isoquinolinium chloro o-phenyl phenate in yield.

If desired, an equivalent amount of lauryl isoquinolinium chloride may be used instead of the bromide in the preceding examples,

' Example III Using techniques similar to that described in Example II, lauryl isoquinolinium compounds were obtained from the sodium salts of tetrachlorophenol, p-chloro m-cresol, p-chloro m-xylenol and from the disodium salts of hexachlorobisphenol and dichlorobisphenol. Yields were 93%, 88%, 89%, 90% and 70% respectively.

In place of lauryl isoquinolinium in the foregoing examples, we may employ equivalent amounts of octyl or decyl isoquinolinium chloride or bromide; equivalent amounts of myristyl, cetyl or stearyl isoquinolinium chloride or bromide, and mixtures thereof.

These compounds, along with those of Examples I and II, are listed in Table I. This table shows their micro biological activity as well as their solubility in water. This microbiological activity was determined by the Standard Tube Dilution Test, described previously, using three different organisms, i.e., Staphylococcus aareus, Salmonella typhosa and Aspergillus niger. All of the products were found to be microbiologically active with respect to these three organisms.

TABLE I.PROPERTIES OF THE REACTION PRODUCTS OF SODIUM SALTS OF VARIOUS CHLORINA'IED PHE- NOLS WITH LAURYL ISOQUINOLINIUM BROMIDE Example IV The product formed according to Example III by reaction of lauryl isoquinolinium bromide with the sodium salt of p-chloro-m-cresol and having a solubility of 0.03 parts per 100 grams of water at room temperature was evaluated against three different fungi by the previously described Standard Tube Dilution Test, the following concentrations being found to be the effective static dilution levels:

Aspergillus niger 1/75,000 Penicillz'um lutem' 1/75,000 Pullularia pullulans l/75,000

Similar static levels were found for the analogous product derived from the reaction of lauryl isoquinolinium bromide with the sodium salt of p-chloro-m-Xylenol prepared by the method of Example III.

Example V A 25 weight percent solution of each of the compounds of Example IV was prepared in ethylene glycol mono butyl ether and mixed with a commercial grade of alkyd base paint containing no other fungicide in the ratio of 4 parts by weight of this solution to 96 parts by weight of paint. Strips of filter paper cut to l x 4" were coated with this paint and allowed to dry. They were then inoculated with a culture of Pullularia pullulans and held in an incubator at 25 C. and 90% relative humidity for three weeks. At the end of this time, no fungus growth was visible,

Example VI Four parts of each of the 25% solutions of the two compounds of Example IV were added to 96 parts of a latex acrylic type paint with thorough stirring and each of the latex emulsions thus prepared was inoculated with a culture of Pullularia pullulans and incubated as in Example V. At the end of three weeks, no fungus growth was visible in the latex.

Example VII To a solution of 7 grams of the sodium salt of nonyl phenol in 70 cc. of water was added, with stirring, 100 cc. of a 10% solution of lauryl isoquinolinium bromide. The mixture was allowed to stand until two distinct layers were formed. The lauryl isoquinolinium nonyl phenate formed the lower layer. This layer was separated and vacuum dried to yield 14 grams of a dark brown paste (87% yield).

Example VIII To a solution of 20 grams of the sodium salt of methyl p-hydroxybenzoate in 200 cc. of water was added, with stirring, a chemically equivalent amount ofa 50% aqueous solution of lauryl isoquinolinium bromide.

The mixture was allowed to stand in a separatory funnel until it separated into two distinct layers. The lauryl isoquinolinium methyl p-hydroxybenzoate formed the lower layer. This lower layer was separated and vacuum dried to yield a dark brown paste in 88.3% yield.

In a similar way the ethyl, propyl, butyl and benzyl p-hydroxybenzoate sodium salts were reacted with lauryl isoquinolinium bromide. The respective yields were 76%, 75%, 71% and 79%. All were dark brown pastes.

Example IX A solution of 14 grams of the sodium salt of o-phenyl phenol in 250 cc. of water was prepared and mixed with 250 cc. of a 10% solution of lauryl isoquinolinium bromide. Two layers formed. The lower layer contained the lauryl isoquinolinium o-phenyl phenate. This layer was separated and vacuum dried to yield 18 grams of a solid brown product. This represented a 47% yield.

In a similar way the sodium salt of p-phenyl phenol gave a 45% yield of a brown paste when reacted with lauryl isoquinolinium bromide.

The sodium salt of p-cresol gave a 98% yield of a dark red paste when reacted with lauryl isoquinolinium bromide.

The sodium salt of phenol when reacted in aqueous solution with a chemically equivalent amount of lauryl isoquinolinium bromide gave a yield of a dark red paste.

Example X To 70 cc. of a 10% aqueous solution of lauryl isoquinolinium bromide in a 250 cc. separatory funnel was added 100 cc. of a 10% solution of the sodium salt of ditertiary butyl p-cresol. These solutions were well mixed by vigorously shaking the separatory funnel. On standing, a dark red oil separated and formed the lower layer. This lower layer was drawn off into an evaporating dish and vacuum dried to give an 80% yield of lauryl isoquinolinium ditertiary butyl p-cresylate, a dark brown paste. The di(lauryl isoquinolinium) salt of bisphenol was also prepared.

Example XI To a 2.5% aqueous solution of the sodium salt of 4,4'-thiobis(6-tertiary butyl o-cresol) was added a chemically equivalent amount of a 10% aqueous solution of lauryl isoquinolinium bromide. On standing, a red oil precipitated to form a separate lower layer. This lower layer was dried to give a 71.5% yield of lauryl isoquinolinium 4,4'-thiobis(6-tertiary butyl o-cresylate).

Example XII To 60 cc. of a 10% aqueous solution of the sodium salt of mixed tertiary butyl phenols was added 134 cc. of a 10% aqueous solution of lauryl isoquinolinium bromide. The product layer was separated and dried to give a 76% yield of a lauryl isoquinolinium tertiary butyl phenolate, a dark red paste.

In a similar way aqueous solutions of the sodium salts of 2,2'-methylene bis(4-methyl-6-tertiary butyl phenol) and 2,2-methylene bis(4-ethyl-6-tertiary butyl phenol) were reacted with lauryl isoquinolinium bromide to give essentially water insoluble salts in yields of 99% and 91%, respectively. The lauryl isoquinolinium salt of 2,6-ditertiary butyl alpha dimethyl amino phenol was also prepared.

7 Example XIII To a solution of 14 grams of the sodium salt of salicylaldehyde in 200 cc. of water was added, with stirring, 379 cc. of a 10% solution of lauryl isoquinolinium bromide. The mixture was allowed to stand and two distinct layers formed. The product layer containing the lauryl isoquinolinium salt of salicylaldehyde was a redbrown oil with a density greater than water. It was separated and vacuum dried to yield a red paste in 79% yield.

Example XIV Using standard bacteriological methods described above, the products described in Examples VII through XIII were tested against Staphylococcus aureus, Salmonella typlzosa and Aspergillus niger for biostasis, referred to respectively as S.a., S.t., and A.n. in the following table. Results of these tests are shown in the followmg Table II.

TABLE II Reciprocal of Static Lauryl Isoquinolinlum Reaction Dilution of Product vs.-

Product With 8.0. St. Ant

Nonyl phenol 10 10 10 Methyl p-hydroxy benzoate. 10 10 10 Ethyl p-hydroxy benzoate 10 10 10 Propyl p-hydroxy benzoate 10 10 10 Butyl p-hydroxy benzoate- 10 10 10 Benzyl p-hydroxy benzoate. 10 10 10 o-Ihenyl phenol 10 10 10 p-Phenyl phenol 10 10 10 p-Cresol 10 10 10 Phenol 10 10 10 Di-t-butyl p-cresol 10 10 10 4,4 thio bis(6-t-butyl o-eresol) 10 10 10 Mixed t-butyl phenols 10 10 2,6 di-t-butyl alpha dimethyl amino para cresol 10 10 10 2, 2 methylene bis (4methyl G-t-butyl phenol) 10 10 10 2,2 methylene bis (tethyl t-fi-butyl phenol) 10 10 10 Salicylaldehyde 10 1O 10 Bis phenol 10 10 10 Example XV A stock shampoo formulation was prepared as follows:

Percent Triethanolamine salt of lauryl sulfate 30 Laurie acid diethanolamine condensate 8 Ethoxylated lanolin 2 Water 60 A second solution was prepared of percent by weight of lauryl isoquinolinium p-chloro m-xylenate in isopropanol.

This isopropanol solution was mixed with the stock shampoo formulation to give a finished product which contained 0.1 weight percent of lauryl isoquinolinium p-chloro m-xylenate. The finished product is a clear, red, slightly viscous foamy liquid which was found effective for the control of dandruff. Any of the higher alkyl isoquinolinium phenolic derivatives listed in the preceding examples having microbiologically active properties may be used in sutficiently active amounts in place of the above xylenate compound. We may also formulate shampoo preparations by directly adding the desired 5.A quaternary ammonium phenate having the strucwherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue of phenol or a substituted phenol whose only acidic group is at least one hydroxyl group, the water solubility of said quaternary ammonium phenate being not in excess of 3 parts by weight per parts of solution at room temperature.

6. Lauryl isoquinolinium pentachlorphenate.

7. Alkyl isoquinolinium tetrachlorphenate, the alkyl having 8 to 18 carbon atoms.

8. Alkyl isoquinolinium p-chloro m-cresylate, the alkyl having 8 to 18 carbon atoms.

9. Alkyl isoquinolinium hexachlorobisphenate, the alkyl having 8 to 18 carbon atoms. 1 10. Alkyl isoquinolinium dichlorobisphenate, the alkyl having 8 to 18 carbon atoms.

11. Lauryl isoquinolinium p-carbomethoxy phenolate.

12. Lauryl isoquinolinium p-carboethoxy phenolate.

13. Lauryl isoquinolinium p-carbopropoxy phenolate.

14. Lauryl isoquinolinium p-carbobutoxy phenolate.

15. Lauryl isoquinolinium p-carbobenzoxy phenolate.

16. Lauryl isoquinolinium paracresylate.

17. Lauryl isoquinolinium phenate.

18. Lauryl isoquinolinium ditertiary butyl p-cresylate.

19. Di(lauryl isoquinolinium) bisphenate.

20. Lauryl isoquinolinium 4,4'-thiobis (6-tertiary butyl o-cresylate) 21. Lauryl isoquinolinium tertiary butyl phenolate.

22. Lauryl isoquinolinium 2,2 methylene bis (4-methyl- 6-tertiary butyl phenolate).

23. Lauryl isoquinolinium 2,2 methylene bis(4-ethyl- 6-.tertiary butyl phenolate).

24. Lauryl isoquinolinium 2,6 dietertiary butyl alpha dimethyl amino phenolate.

25. Lauryl isoquinolinium salt of salicylaldehyde.

26. Lauryl isoquinolinium bisphenate.

27. Lauryl isoquinolinium 2,6 di-t-butyl alpha dimethyl amino para cresylate.

28. Lauryl isoquinolinium d-t-butyl p-cresylate.

29. Lauryl isoquinolinium p-phenyl phenate.

References Cited by the Examiner UNITED STATES PATENTS 2,344,886 3/1944 Lieber 260567 .6 2,383,775 8/1945 Craig 260567.6 XR 2,395,989 3/1946 Bock 260567.6 2,541,816 2/ 1951 Glarum et a1 260567.5 2,706,195 4/1955 Niederhauser 167--22 2,850,492 9/1962 Erskine 260124- 2,946,796 7/ 1960 Rudner 260286 2,970,999 2/1961 Rudner 260286 XR 3,108,036 10/1963 Molnar 167-22 ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, HENRY R. JILES, Examiners. D. A. DAUS, Assistant Examiner. 

1. LAURYL ISOQUINOLINIUM CHLORO O-PHENYL PHENATE.
 5. A QUATERNARY AMMONIUM PHENATE HAVING THE STRUCTURE: 